Crystal structures of four organic salts of trihexyphenidyl at 90 K

The low-temperature crystal structures of four organic salts of the anti-spasmodic drug trihexyphenidyl are presented.

The syntheses and crystal structure studies of four organic salts of trihexyphenidyl, viz., trihexyphenidylium [1-(3-cyclohexyl-3-hydroxy-3-phenylpropyl)piperidin-1-ium] 4-nitrobenzoate, C 20 H 32 NO + ÁC 7 H 4 NO 4 À (I), trihexyphenidylium 4-hydroxybenzoate, C 20 H 32 NO + ÁC 7 H 5 O À (II), trihexyphenidylium 4-bromobenzoate, C 20 H 32 NO + ÁC 7 H 4 BrO 2 À (III), and trihexyphenidylium thiophene-2-carboxylate hemihydrate, 2C 20 H 32 NO + Á2C 5 H 3 O 2 S À ÁH 2 O (IV), conducted at 90 K are described. Structures I, II, and III are solvent free with one cation-anion pair per asymmetric unit, while IV crystallizes as a hemihydrate, having two cation-anion pairs and one water of crystallization in its asymmetric unit. Structures I and III exhibit configurational disorder of the cation. Structure IV also exhibits disorder, but only of the thiophene-2-carboxylate anions. Structure II is a non-merohedric twin by a twofold rotation about [403]. The main supramolecular motifs in I, II, and III are similar R 2 2 (10) rings between cation-anion pairs, although their packing within the crystals is distinct. As a consequence of having two cation-anion pairs and a water molecule in its asymmetric unit, the packing in IV is by far the most complex of the four structures, its hydrogen-bonding patterns being quite different from I, II, or III. In all the crystals studied, N-HÁ Á ÁO, O-HÁ Á ÁO, and C-HÁ Á ÁO interactions are observed, plus C-HÁ Á ÁBr close contacts for III.

Structural commentary
Individual neutral trihexyphenidyl molecules contain a chiral carbon atom. In structures I, II, III, IV, each trihexyphenidylium cation also includes a chiral carbon, with atoms C1 (C1A and C1B in IV) being the stereogenic centre. Nevertheless, medicinal formulations are racemic, and all four crystal structures (Figs. 1-4) determined here are centrosymmetric and therefore also strictly racemic. Structures I, II, and III are solvent free with one cation-anion pair per asymmetric unit, while IV crystallized as a hemihydrate, having two cation-anion pairs and one water of crystallization in its asymmetric unit.
Structures I and III exhibit configurational disorder (see e.g. Parkin et al., 2023;Vinaya et al., 2023)  An ellipsoid plot (50%) probability of II. Hydrogen bonds are shown as dashed lines.

Figure 3
An ellipsoid plot (50%) probability of III. Hydrogen bonds are shown as dashed lines. To enhance clarity, only one component of disorder for the cation is shown.

Figure 4
An ellipsoid plot (50%) probability of IV. Hydrogen bonds are shown as dashed lines. To enhance clarity, only one component of disorder for the anions is shown.  (9)]. The treatment of disorder and twinning are described in more detail in section 6 (Refinement).
The conformations of the trihexyphenidylium cations are determined, in large part, by torsion angles about the C1-C2, C2-C3, C3-N1, C1-C9, and C1-C15 bonds. These are quantified in Table 1, although for ease of comparison, the variability in cation conformations is better illustrated by an overlay plot, shown in Fig. 6.

Supramolecular features
The main supramolecular motifs in I, II, and III are R  Table 1 Conformation-defining torsion angles ( ) for trihexyphenylidium cations in I, II, III, IV.

Figure 5
Configurational disorder of the trihexyphenidylium cation in I showing the superposition of phenyl and cyclohexyl rings. The disorder in III is similar. Hydrogen atoms are omitted.

Figure 6
An overlay of five independent trihexyphenidylium cations from structures I, II, III, and IV, showing the conformational variability.

Figure 7
A partial packing plot of I, viewed approximately down the a-axis. Hydrogen bonds are drawn as dotted lines. Hydrogen atoms not involved in hydrogen bonds are omitted.
x À 1, y, z] contact between molecules adjacent along the aaxis direction. See Table 2 for details.
In II, the 4-hydroxy group of the anion is also involved in hydrogen bonding (Fig. 8). Atom O3 of the carboxylate acts as a bifurcated acceptor for the N1-H1NÁ Á ÁO3 hydrogen bond within the R 2 2 (10) ring and for an O4 ii -H4O ii Á Á ÁO3 [symmetry code: (ii) x, Ày, z À 1 2 ] hydrogen bond. There are also a few weaker C-HÁ Á ÁO interactions. All these interactions are quantified in Table 3.
In III, in addition to the aforementioned ring motif, there are short contacts between C3-H3A and Br1 of a screwrelated (Àx + 3 2 , y + 1 2 , Àz + 3 2 ) anion and between C4-H4A and O3 of a translation-related (x À 1, y, z) anion. Full details are given in Table 4. A view of the packing is shown in Fig. 9.
As a result of having two cation-anion pairs and a water molecule in the asymmetric unit, the packing in IV is by far the most complex of the four structures. Its hydrogen-bonding patterns are quite different from I, II, or III. In fact the hydrogen-bonding motifs involving the 'A-C' and 'B-D' cation-anion pairs are themselves distinct. For the 'A' cation,  Table 2 Hydrogen-bond geometry (Å , ) for I.   Symmetry codes: (i) Àx þ 3 2 ; y þ 1 2 ; Àz þ 3 2 ; (ii) x À 1; y; z.

Figure 8
A partial packing plot of II, viewed approximately down the b-axis. Hydrogen bonds are drawn as dotted lines. Hydrogen atoms not involved in hydrogen bonds are omitted.

Figure 9
A partial packing plot of III, viewed approximately down the a-axis. Hydrogen bonds are drawn as dotted lines. Hydrogen atoms not involved in hydrogen bonds are omitted. Table 5 Hydrogen-bond geometry (Å , ) for IV.  ) to O2C of a translationrelated (via x + 1, y, z) anion. These combine to form A-C cation-anion chains that extend parallel to the a-axis (Fig. 10, upper chain). The B-D cation-anion pair plus the water molecule form an R 3 3 (12) hydrogen-bonded ring motif that includes N1B-H1NBÁ Á ÁO1D, O1B-H1OBÁ Á ÁO1W, and O1W-H2W1Á Á ÁO2D within the chosen asymmetric unit (Table 5, Figs. 4 and 10). The water molecule also forms a hydrogen bond to O1D of a translation-related (x + 1, y, z) anion. The net result of these hydrogen bonds are cationanion-water chains that also propagate along the a-axis direction (Fig. 10, lower chain). The only contacts between these two types of chain are weak (Table 5).

Database survey
A search within the Cambridge Structural Database (CSD, v5.43 including all updates through November 2022;Groom et al., 2016) for an unsubstituted trihexyphenidyl structure fragment returned 16 hits, but only five of them bear any similarity to the trihexyphenidylium cation in I, II, III, and IV. CSD entry THEXPL (Camerman & Camerman, 1972) is a single-crystal structure of neutral trihexyphenidyl. Refcode KUZDIT (Maccaroni et al., 2010) is trihexyphenidyl hydrochloride, obtained via powder diffraction, and GODJAN (Shaibah et al., 2019) is a single-crystal study of the trihexyphenidylium 3,5-dinitrobenzoate salt. The remaining two structures are PCYDIN10 (Camerman & Camerman, 1971) and DODWAU (Tacke et al., 1986). The former is the antipsychotic medication procyclidine hydrochloride, which has a pyrrolidinium ring in place of the piperidinium ring in I, II, III, and IV. The latter is (R)-tricyclamol iodide, which has an Nmethyl-pyrrolidinium ring.

Refinement
Crystal data, data collection, and refinement statistics are given in Table 6. For all structures, diffraction data were collected with the crystals at 90 K. Non-disordered hydrogen atoms were located in difference-Fourier maps. Those bound to nitrogen or oxygen were refined freely, but carbon-bound hydrogens were included using riding models with constrained distances of 0.95 Å (Csp 2 -H), 0.99 Å (R 2 CH 2 ), and 1.00 Å (R 3 CH) using U iso (H) values constrained to 1.2U eq of the attached carbon atom. Cation disorder in I and III was modelled using similar combinations of restraints (SHELXL commands SADI, SAME, DFIX, FLAT) and constraints (SHELXL command EADP). Disorder of the thiophene-2carboxylate anions in IV corresponded to a $180 flip of the thiophene ring, which is common for thiophene, and was modelled using geometry restraints (SAME and FLAT) and displacement parameter constraints (EADP). Structure II was twinned by non-merohedry, corresponding to a twofold rotation about the real-space direction [403]. Diffraction data were integrated using two orientation matrices and scaled/merged following standard procedures (see e.g. Sevvana et al., 2019), and the model refined against both twin components in the usual manner (SHELXL-format HKLF 5 datafile and a BASF parameter to define their relative volume fractions).